Luteinizing hormone releasing hormone (LRH) is a known decapeptide presenting the amino acid sequence L-(5-oxo-prolyl)-L-histidyl-L-tryptophyl-L-seryl-L-tyrosyl-glycyl-L-leucyl -L-arginyl-L-prolyl-glycinamide ##STR1## Chang et al. J. Med. Chem. 15, 623 (1972). LRH is endogenously produced by the hypothalamus and stimulates the secretion of the pituitary gonadotropins, luteinizing hormone and follicle stimulating hormone. LRH is presently employed clinically as a diagnostic and therapeutic agent for treatment of infertility by inducing ovulation and in other hypogonadotropic and hypogonadal disorders.
Recently, several LRH agonists have been synthesized. In 1972, Fujino et al., Biochem. Biophys. Res. Commun. 49, 863 reported that the nonapeptide des-Gly-NH.sub.2.sup.10 -[Pro.sup.9 -ethylamide]LRH has five times the activity of LRH itself. Monahan et al., Biochemistry, 12, 4616 (1973), reports that replacement of the Gly.sup.6 moiety in LRH by D-Ala.sup.6 to form the decapeptide [D-Ala.sup.6 ]LRH increased the potency of the parent hormone by from 350 to 450 percent. In 1974, Coy et al., Biochem. Biophys. Res. Commun. 57, 335, reported that the nonapeptide [D-Ala.sup.6, des-Gly-NH.sub.2.sup.10 ]LRH ethylamide was markedly more potent than LRH and the previously known LRH agonists. In 1974, Fujino et al., Biochem. Biophys. Res. Comm. 57, 1248, reported that [Phe.sup.5, D-Ala.sup.6, des-Gly.sup.10 ]LRH ethylamide possessed activity comparable to [D-Ala.sup.6, des-Gly.sup.10 ]LRH ethylamide in the order of 50 times that of LRH itself. Fujino et al. have also reported in Biochem. Biophys. Res. Comm. 60, 406(1974) that [Ile.sup.5, D-Ala.sup.6, des-Gly.sup.10 ]LRH ethylamide provides intense activity as an ovulation-inducing LRF agonist; [DL-Leu.sup.6 ]LRH and [DL-Leu.sup.6, des-Gly.sup.10 ]LRH ethylamide exhibited 8 and 20 times the ovulation inducing activity, respectively, of LRH and that an entire series of polypeptides, modified by substituting for the 6-amino acid of LRH, a D-ala, D-.alpha.-aminobutyric acid, D-norvaline, D-Leu, D-Phe or D-Ser group with or without the des-Gly-NH.sub.2.sup.10 modification with formation of the corresponding prolylethylamide, and with several variations substituting Phe or Ile for the tyrosyl in 5-position of the polypeptide, led to the formation of potent LRH agonists.
Another LRH agonist is disclosed in the copending U.S. patent application of McKinley and Sarantakis Ser. No. 472,269 which discloses [D-Lys.sup.6 ]LRH prepared by solid phase methodology involving the following steps: